WO2005102348A1 - Composition and method of decreasing renal ischemic damage - Google Patents

Composition and method of decreasing renal ischemic damage Download PDF

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Publication number
WO2005102348A1
WO2005102348A1 PCT/US2005/013175 US2005013175W WO2005102348A1 WO 2005102348 A1 WO2005102348 A1 WO 2005102348A1 US 2005013175 W US2005013175 W US 2005013175W WO 2005102348 A1 WO2005102348 A1 WO 2005102348A1
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composition
agent
phosphodiesterase inhibitor
phosphodiesterase
inhibitor
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PCT/US2005/013175
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French (fr)
Inventor
Dalton D. Baldwin
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Loma Linda University
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Application filed by Loma Linda University filed Critical Loma Linda University
Priority to AU2005235306A priority Critical patent/AU2005235306B2/en
Priority to EP05737742A priority patent/EP1737465A4/en
Priority to CA2563693A priority patent/CA2563693C/en
Publication of WO2005102348A1 publication Critical patent/WO2005102348A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • kidney removal for transplantation is also associated with ischemic damage.
  • ischemic damage In the United States alone, there are approximately 9,000 kidney transplants each year. Of these, approximately 500 are found to have significant ischemic damage during transplantation.
  • the mechanism of renal ischemic damage is partly understood. Animal studies have demonstrated that deliberately decreasing renal blood flow and glomerular filtration rate using CO 2 pneumoperitoneum preconditioning prior to the ischemic event significantly decreases the area and amount of ischemic damage. The effect of such limited ischemic preconditioning appears to lead to an increase in nitric oxide metabolites due to an increase in endothelial nitric oxide synthase.
  • the one or more than one dose of the agent is between about 2 doses and 6 doses. In another embodiment, the one or more than one dose of the agent is three doses. In one embodiment, the one or more than one dose is a plurality of doses administered between about 1 minute and 2 days apart. In another embodiment, the one or more than one dose is a plurality of doses administered between about 10 minutes and 1 day apart. In another embodiment, the one or more than one dose is a plurality of doses administered between about 30 minutes and 4 hours apart. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage comprising two or more than two phosphodiesterase inhibitors.
  • the two or more than two phosphodiesterase inhibitors are selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In another embodiment, at least one of the two or more than two phosphodiesterase inhibitors is a type 5 phosphodiesterase inhibitor. In one embodiment, at least one of the two or more than two phosphodiesterase inhibitors is selected from the group consisting of sildenafil, tadalafil and vardenafil. In one embodiment, the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 1 mg and 1 g.
  • the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 25 mg to 100 mg. In another embodiment, the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage comprising two or more than two HMG- CoA reductase inhibitors.
  • At least one of the two or more than two HMG-CoA reductase inhibitors is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
  • the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 10 mg and 200 mg.
  • the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 25 mg to 100 mg.
  • the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent.
  • a composition for decreasing renal ischemic damage comprising one or more than one phosphodiesterase inhibitor, and one or more than one HMG-CoA reductase inhibitor.
  • At least one of the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
  • the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 25 mg to 100 mg.
  • the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 25 mg to 100 mg. In another embodiment, the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent.
  • the term “comprise” and variations of the term, such as “comprising” and “comprises,” are not intended to exclude other additives, components, integers or steps.
  • the term “organism” includes a human.
  • a method of decreasing renal ischemic damage in an organism subjected to an ischemic event In one embodiment, the organism is serving as a kidney donor during renal transplantation, and the ischemie «vent is removal of the kidney for transplantation into another organism. The method comprises, first, identifying an organism having a kidney that is susceptible to renal ischemic damage from an ischemic event.
  • the method comprises administering to the organism one or more than one effective dose of an agent prior to the ischemic event.
  • Administering to the organism the one or more than one effective dose of the agent serves to at least partially protect the organism's kidney from damage during a subsequent ischemic event.
  • the agent is a phosphodiesterase inhibitor.
  • the agent is a composition comprising a phosphodiesterase inhibitor.
  • the phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
  • the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor.
  • the agent is an HMG-CoA reductase inhibitor.
  • the agent is a composition comprising an HMG-CoA reductase inhibitor.
  • the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
  • the agent is a composition comprising both one or more than one phosphodiesterase inhibitor and one or more than one HMG-CoA reductase inhibitor.
  • the one or more than one phosphodiesterase inhibitor selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
  • the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor.
  • the phosphodiesterase inhibitor appears to protect the organism's kidney from a subsequent ischemic event by increasing nitric oxide levels within the organism, thereby mimicking the action of limited ischemic preconditioning.
  • the HMG-CoA reductase inhibitors appear to protect the organism's kidney from a subsequent ischemic event by acting as a nitric oxide donor or through the HMG-CoA reductase inhibition pathway.
  • the phosphodiesterase inhibitor is selected from the group consisting of sildenafil (Viagra ® , available from Pfizer, Inc., New York, NY US), tadalafil (Cialis ® ; available from Lilly ICOS, L.L.C. Delaware, MD US) and vardenafil (Levitra ® , available from Bayer Aktiengesellschaft, Germany), though other phosphodiesterase inhibitors can be used, as will be understood by those with skill in the art with reference to this disclosure.
  • the dose of the agent for an adult human is between about 1 mg and 1 g. ' In another embodiment, the dose of the agent for an adult human is between about 10 mg and 200 mg. In another embodiment, the dose of the agent for an adult human is between about 25 mg to 100 mg. In one embodiment, the organism has a body weight and the dose of the agent is between about 0.015 mg/kg body weight and 15 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent between about 0.15 mg/kg body weight and 3 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent is between about 0.5 mg/kg body weight and 1.5 mg/kg body weight.
  • the agent is administered orally, though other routes of administration are also within the scope of this invention, as will be understood by those with skill in the art with reference to this disclosure including administration by a route selected from the group consisting of administration by skin patch, administration by subcutaneous injection, administration by an inhaled preparation and direct intravenous administration.
  • the one or more than one dose of the agent is between about 1 dose and 10 doses.
  • the one or more than one dose of the agent is between about 2 doses and 6 doses.
  • the one or more than one dose of the agent is three doses.
  • the one or more than one dose is a plurality of doses administered between about 1 minute and 2 days apart.
  • the one or more than one dose is a plurality of doses administered between about 10 minutes and 1 day apart. In another preferred embodiment, the one or more than one dose is a plurality of doses administered between about 30 minutes and 4 hours apart.
  • a composition for decreasing renal ischemic damage comprises two or more than two phosphodiesterase inhibitors. In a preferred embodiment, the phosphodiesterase inhibitors are selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
  • the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil.
  • the composition comprises two or more than two HMG- CoA reductase inhibitors.
  • the HMG-CoA reductase inhibitors are selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
  • the composition of the present invention can also comprise one or more than one additional substance, such a binding agent, a coloring agent, an enteric coating and a flavoring agent.
  • the composition is preferably configured to be administered orally, however, it can also be configured to be administered by skin patch, subcutaneous injection, inhaled preparations or direct intravenous administration, among other routes, as will be understood by those with skill in the art with reference to this disclosure.
  • EXAMPLE I METHOD OF DECREASING RENAL ISCHEMIC DAMAGE DURING TRANSPLANTATION
  • the method of the present invention can be used as follows.

Abstract

A method of decreasing renal ischemic damage comprising a) identifying an organism having a kidney that is susceptible to renal ischemic damage from an ischemic event; and b) administering to the organism one or more than one effective dose of an agent prior to the ischemic event; where administering to the organism the one or more than one effective dose of the agent serves to at least partially protect the organism's kidney from damage during a subsequent ischemic event. A composition for decreasing renal ischemic damage comprising one or more than one phosphodiesterase inhibitor, and one or more than one HMG-CoA reductase inhibitor.

Description

COMPOSITION AND METHOD OF DECREASING RENAL ISCHEMIC DAMAGE
CROSS-REFERENCE TO RELATED APPLICATIONS The present Application claims the benefit of United States Provisional Patent Application 60/563,772, titled "Composition and Method of Decreasing Renal Ischemic Damage" filed April 19, 2004; and claims the benefit of United States Provisional Patent Application 60/578,531, titled "Composition and Method of Decreasing Renal Ischemic Damage" filed June 9, 2004; the contents of which are incorporated in this disclosure by reference in their entirety. BACKGROUND There are a variety of diseases and conditions that cause ischemia of the kidney, leading to kidney dysfunction. These diseases and conditions include partial nephrectomy for tumor and congenital anomalies, renal trauma, iatrogenic renal injuries and renal vascular surgery. Further, kidney removal for transplantation is also associated with ischemic damage. In the United States alone, there are approximately 9,000 kidney transplants each year. Of these, approximately 500 are found to have significant ischemic damage during transplantation. There is, at present, no practical and effective method known to decrease renal ischemic damage associated with these diseases and conditions. The mechanism of renal ischemic damage is partly understood. Animal studies have demonstrated that deliberately decreasing renal blood flow and glomerular filtration rate using CO2 pneumoperitoneum preconditioning prior to the ischemic event significantly decreases the area and amount of ischemic damage. The effect of such limited ischemic preconditioning appears to lead to an increase in nitric oxide metabolites due to an increase in endothelial nitric oxide synthase. Disadvantageously, however, deliberately causing limited ischemia prior to an ischemic event is not a practical method when preventing renal ischemic damage in the context of a live kidney donor, among other circumstances. Therefore, there is a need for another method of decreasing renal ischemic damage in an organism, including a human. SUMMARY According to one embodiment of the present invention, there is provided a method of decreasing renal ischemic damage. The method comprises, first, identifying an organism having a kidney that is susceptible to renal ischemic damage from an ischemic event, and second, administering to the organism one or more than one effective dose of an agent prior to the ischemic event; where administering to the organism the one or more than one effective dose of the agent serves to at least partially protect the organism's kidney from damage during a subsequent ischemic event. In one embodiment, the ischemic event is removal of the kidney for transplantation into another organism. In one embodiment, the agent is a phosphodiesterase inhibitor. In another embodiment, the agent is a composition comprising a phosphodiesterase inhibitor. In one embodiment, the phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In another embodiment, the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor. In another embodiment, the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil. In one embodiment, the agent is an HMG-CoA reductase inhibitor. In another embodiment, the agent is a composition comprising an HMG-CoA reductase inhibitor. In one embodiment, the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In one embodiment, the agent is a composition comprising both one or more than one phosphodiesterase inhibitor and one or more than one HMG-CoA reductase inhibitor. In one embodiment, the phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In another embodiment, the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor. In another embodiment, the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil. In one embodiment, the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In one embodiment, the dose of the agent is between about 1 mg and 1 g. In another embodiment, the dose of the agent is between about 10 mg and 200 mg. In another embodiment, the dose of the agent is between about 25 mg to 100 mg. In one embodiment, the organism has a body weight and the dose of the agent is between about 0.015 mg/kg body weight and 15 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent is between about 0.15 mg/kg body weight and 3 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent is between about 0.5 mg/kg body weight and 1.5 mg/kg body weight. In one embodiment, the agent is administered orally. In another embodiment, the agent is administered by a route selected from the group consisting of administration by skin patch, administration by subcutaneous injection, administration by an inhaled preparation and direct intravenous administration. In one embodiment, the one or more than one dose of the agent is between about 1 dose and 10 doses. In another embodiment, the one or more than one dose of the agent is between about 2 doses and 6 doses. In another embodiment, the one or more than one dose of the agent is three doses. In one embodiment, the one or more than one dose is a plurality of doses administered between about 1 minute and 2 days apart. In another embodiment, the one or more than one dose is a plurality of doses administered between about 10 minutes and 1 day apart. In another embodiment, the one or more than one dose is a plurality of doses administered between about 30 minutes and 4 hours apart. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage comprising two or more than two phosphodiesterase inhibitors. In one embodiment, the two or more than two phosphodiesterase inhibitors are selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In another embodiment, at least one of the two or more than two phosphodiesterase inhibitors is a type 5 phosphodiesterase inhibitor. In one embodiment, at least one of the two or more than two phosphodiesterase inhibitors is selected from the group consisting of sildenafil, tadalafil and vardenafil. In one embodiment, the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 25 mg to 100 mg. In another embodiment, the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage comprising two or more than two HMG- CoA reductase inhibitors. In one embodiment, at least one of the two or more than two HMG-CoA reductase inhibitors is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In one embodiment, the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the two or more than two HMG-CoA reductase inhibitors is between about 25 mg to 100 mg. In another embodiment, the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage comprising one or more than one phosphodiesterase inhibitor, and one or more than one HMG-CoA reductase inhibitor. In one embodiment, at least one of the one or more than one phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In another embodiment, at least one of the one or more than one phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor. In another embodiment, at least one of the one or more than one phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil. In another embodiment, at least one of the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In one embodiment, the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 25 mg to 100 mg. In one embodiment, the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 1 mg and 1 g. In another embodiment, the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 10 mg and 200 mg. In another embodiment, the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 25 mg to 100 mg. In another embodiment, the composition further comprises one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent. DESCRIPTION According to one embodiment of the present invention, there is provided a method of decreasing renal ischemic damage in an organism, including a human, including decreasing renal ischemic damage in an organism serving as a kidney donor during renal transplantation. The method comprises administering to the organism one or more than one effective dose of one or more than one phosphodiesterase inhibitor, or one or more than one HMG-CoA reductase inhibitor, or a combination of one or more phosphodiesterase inhibitor and one or more than one HMG-CoA reductase inhibitor. In a preferred embodiment, the method comprises administering to the organism one or more than one effective dose of a composition according to the present invention. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage. The method and composition will now be disclosed in detail. As used in this disclosure, the term "comprise" and variations of the term, such as "comprising" and "comprises," are not intended to exclude other additives, components, integers or steps. As used in this disclosure, the term "organism" includes a human. According to one embodiment of the present invention, there is provided a method of decreasing renal ischemic damage in an organism subjected to an ischemic event. In one embodiment, the organism is serving as a kidney donor during renal transplantation, and the ischemie «vent is removal of the kidney for transplantation into another organism. The method comprises, first, identifying an organism having a kidney that is susceptible to renal ischemic damage from an ischemic event. Next, the method comprises administering to the organism one or more than one effective dose of an agent prior to the ischemic event. Administering to the organism the one or more than one effective dose of the agent serves to at least partially protect the organism's kidney from damage during a subsequent ischemic event. In one embodiment, the agent is a phosphodiesterase inhibitor. In a preferred embodiment, the agent is a composition comprising a phosphodiesterase inhibitor. In a preferred embodiment, the phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In a particularly preferred embodiment, the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor. In another embodiment the agent is an HMG-CoA reductase inhibitor. In a preferred embodiment, the agent is a composition comprising an HMG-CoA reductase inhibitor. In one embodiment, the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In a preferred embodiment, the agent is a composition comprising both one or more than one phosphodiesterase inhibitor and one or more than one HMG-CoA reductase inhibitor. In a preferred embodiment, the one or more than one phosphodiesterase inhibitor selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In a particularly preferred embodiment, the phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor. Though not intending to be limited to any particular theory, the phosphodiesterase inhibitor appears to protect the organism's kidney from a subsequent ischemic event by increasing nitric oxide levels within the organism, thereby mimicking the action of limited ischemic preconditioning. The HMG-CoA reductase inhibitors appear to protect the organism's kidney from a subsequent ischemic event by acting as a nitric oxide donor or through the HMG-CoA reductase inhibition pathway. In one embodiment, the phosphodiesterase inhibitor is selected from the group consisting of sildenafil (Viagra®, available from Pfizer, Inc., New York, NY US), tadalafil (Cialis®; available from Lilly ICOS, L.L.C. Delaware, MD US) and vardenafil (Levitra®, available from Bayer Aktiengesellschaft, Germany), though other phosphodiesterase inhibitors can be used, as will be understood by those with skill in the art with reference to this disclosure. In another embodiment, the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium (Lipitor®, available from Pfizer, Inc., New York, NY US), fluvastatin sodium (Lescol® available from Novartis AG Corporation, Basel, Switzerland), lovastatin (Mevacor® available from Merck & Co., Inc., NJ US), pitavastatin calcium (Livalo available from Kowa Company Ltd., Naka-ku Nagoya JP), pravastatin sodium (Pravachol® available from Bristol-Myers Squibb Company, New York, NY US), simvastatin (Zocor® available from Merck & Co., Inc., Whitehouse Station, NJ US), and rosuvastatin calcium (Crestor®, available from IPR Pharmaceuticals Inc., Puerto Rico US), though other HMG-CoA reductase inhibitors can be used, as will be understood by those with skill in the art with reference to this disclosure. In one embodiment, the dose of the agent for an adult human is between about 1 mg and 1 g. 'In another embodiment, the dose of the agent for an adult human is between about 10 mg and 200 mg. In another embodiment, the dose of the agent for an adult human is between about 25 mg to 100 mg. In one embodiment, the organism has a body weight and the dose of the agent is between about 0.015 mg/kg body weight and 15 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent between about 0.15 mg/kg body weight and 3 mg/kg body weight. In another embodiment, the organism has a body weight and the dose of the agent is between about 0.5 mg/kg body weight and 1.5 mg/kg body weight. In a preferred embodiment, the agent is administered orally, though other routes of administration are also within the scope of this invention, as will be understood by those with skill in the art with reference to this disclosure including administration by a route selected from the group consisting of administration by skin patch, administration by subcutaneous injection, administration by an inhaled preparation and direct intravenous administration. In a preferred embodiment, the one or more than one dose of the agent is between about 1 dose and 10 doses. In another embodiment, the one or more than one dose of the agent is between about 2 doses and 6 doses. In another embodiment, the one or more than one dose of the agent is three doses. In a preferred embodiment, the one or more than one dose is a plurality of doses administered between about 1 minute and 2 days apart. In another preferred embodiment, the one or more than one dose is a plurality of doses administered between about 10 minutes and 1 day apart. In another preferred embodiment, the one or more than one dose is a plurality of doses administered between about 30 minutes and 4 hours apart. According to another embodiment of the present invention, there is provided a composition for decreasing renal ischemic damage. In one embodiment, the composition comprises two or more than two phosphodiesterase inhibitors. In a preferred embodiment, the phosphodiesterase inhibitors are selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor. In a preferred embodiment, the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil. In another embodiment, the composition comprises two or more than two HMG- CoA reductase inhibitors. In a preferred embodiment, the HMG-CoA reductase inhibitors are selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In another embodiment, the composition comprises two or more than two agents selected from the group consisting of sildenafil, tadalafil, vardenafil, atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin. In one embodiment, the amount of each agent in the composition is between about 1 mg and 1 g. In another embodiment, the amount of each agent in the composition is between about 10 mg and 200 mg. In another embodiment, the amount of each agent in the composition is between about 25 mg to 100 mg. As will be understood by those with skill in the art with reference to this disclosure, the composition of the present invention can also comprise one or more than one additional substance, such a binding agent, a coloring agent, an enteric coating and a flavoring agent. The composition is preferably configured to be administered orally, however, it can also be configured to be administered by skin patch, subcutaneous injection, inhaled preparations or direct intravenous administration, among other routes, as will be understood by those with skill in the art with reference to this disclosure. EXAMPLE I METHOD OF DECREASING RENAL ISCHEMIC DAMAGE DURING TRANSPLANTATION The method of the present invention can be used as follows. Patient 1 , a 60-kg male, is a suitable live donor for a kidney for patient 2, also a 60-kg male and a dialysis patient having no significant residual natural kidney function. Patient 1 is administered three 100 mg doses of sildenafil orally, once a day for 3 days prior to the surgery to remove the donated kidney, thereby decreasing the risk of renal ischemic damage to the donated kidney. The donated kidney is then harvested and implanted in patient 2.
Although the present invention has been discussed in considerable detail with reference to certain preferred embodiments, other embodiments are possible. Therefore, the scope of the appended claims should not be limited to the description of preferred embodiments contained herein.

Claims

WHAT IS CLAIMED IS: 1. A method of decreasing renal ischemic damage comprising: a) identifying an organism having a kidney that is susceptible to renal ischemic damage from an ischemic event; and b) administering to the organism one or more than one effective dose of an agent prior to the ischemic event; where administering to the organism the one or more than one effective dose of the agent serves to at least partially protect the kidney from damage during a subsequent ischemic event.
2. The method of claim 1, where the ischemic event is removal of the kidney for transplantation into another organism.
3. The method of claim 1, where the agent is a phosphodiesterase inhibitor.
4. The method of claim 1, where the agent is a composition comprising a phosphodiesterase inhibitor.
5. The method of claim 3 or claim 4, where the agent is a phosphodiesterase inhibitor selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
6. The method of claim 3 or claim 4, where the agent is a type 5 phosphodiesterase inhibitor.
7. The method of claim 3 or claim 4, where the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil.
8. The method of claim 1, where the agent is one or more than one HMG-CoA reductase inhibitor.
9. The method of claim 1 , where the agent is a composition comprising one or more than one HMG-CoA reductase inhibitor.
10. The method of claim 8 or claim 9, where the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
11. The method of claim 1 , where the agent is a composition comprising both one or more than one phosphodiesterase inhibitor and one or more than one HMG-CoA reductase inhibitor.
12. The method of claim 10, where the one or more than one phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
13. The method of claim 12, where the one or more than one phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor.
14. The method of claim 12, where the one or more than one phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil.
15. The method of claim 12, where the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
16. The method of claim 1 , where the dose of the agent is between about 1 mg and 1 g-
17. The method of claim 1, where the dose of the agent is between about 10 mg and
200 mg.
18. The method of claim 1 , where the dose of the agent is between about 25 mg to 100 mg.
19. The method of claim 1 , where the organism has a body weight and the dose of the agent is between about 0.015 mg/kg body weight and 15 mg/kg body weight.
20. The method of claim 1 , where the organism has a body weight and the dose of the agent is between about 0.15 mg/kg body weight and 3 mg/kg body weight.
21. The method of claim 1 , where the organism has a body weight and the dose of the agent is between about 0.5 mg/kg body weight and 1.5 mg/kg body weight.
22. The method of claim 1, where the agent is administered orally.
23. The method of claim 1, where the agent is administered by a route selected from the group consisting of administration by skin patch, administration by subcutaneous injection, administration by an inhaled preparation and direct intravenous administration.
24. The method of claim 1, where the one or more than one dose of the agent is between about 1 dose and 10 doses.
25. The method of claim 1 , where the one or more than one dose of the agent is between about 2 doses and 6 doses.
26. The method of claim 1 , where the one or more than one dose of the agent is three doses.
27. The method of claim 1, where the one or more than one dose is a plurality of doses administered between about 1 minute and 2 days apart.
28. The method of claim 1, where the one or more than one dose is a plurality of doses administered between about 10 minutes and 4 hours apart.
29. The method of claim 1, where the one or more than one dose is a plurality of doses administered between about 30 minutes and 1 hour apart.
30. A composition for decreasing renal ischemic damage comprising two or more than two -phosphodiesterase inhibitors.
31. The composition of claim 30, where the two or more than two phosphodiesterase inhibitors are selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
32. The composition of claim 30, where at least one of the two or more than two phosphodiesterase inhibitors is a type 5 phosphodiesterase inhibitor.
33. The composition of claim 30, where at least one of the two or more than two phosphodiesterase inhibitors is selected from the group consisting of sildenafil, tadalafil and vardenafil.
34. The composition of claim 30, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 1 mg and 1 g.
35. The composition of claim 30, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 10 mg and 200 mg.
36. The composition of claim 30, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 25 mg to 100 mg.
37. The composition of claim 30, further comprising one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent.
38. A composition for decreasing renal ischemic damage comprising two or more than twόΗMG-CoA reductase inhibitors.
39. The composition of claim 38, where at least one of the two or more than two HMG-CoA reductase inhibitors is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
40. The composition of claim 38, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 1 mg and 1 g.
41. The composition of claim 38, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 10 mg and 200 mg.
42. The composition of claim 38, where the amount of at least one of the two or more than two phosphodiesterase inhibitors is between about 25 mg to 100 mg.
43. The composition of claim 38, further comprising one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent.
44. A composition for decreasing renal ischemic damage comprising one or more than one phosphodiesterase inhibitor, and one or more than one HMG-CoA reductase inhibitor.
45. The composition of claim 44, where at least one of the one or more than one phosphodiesterase inhibitor is selected from the group consisting of a type 3 phosphodiesterase inhibitor, a type 4 phosphodiesterase inhibitor, a type 5 phosphodiesterase inhibitor and a type 9 phosphodiesterase inhibitor.
46. The composition of claim 44, where at least one of the one or more than one phosphodiesterase inhibitor is a type 5 phosphodiesterase inhibitor.
47. The composition of claim 44, where at least one of the one or more than one phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil.
48. The composition of claim 44, where at least one of the one or more than one HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, fluvastatin sodium, lovastatin, pitavastatin calcium, pravastatin sodium, rosuvastatin calcium and simvastatin.
49. The composition of claim 44, where the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 1 mg and 1 g.
50. The composition of claim 44, where the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 10 mg and 200 mg.
51. The composition of claim 44, where the amount of at least one of the one or more than one phosphodiesterase inhibitor is between about 25 mg to 100 mg.
52. The composition of claim 44, where the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 1 mg and 1 g.
53. The composition of claim 44, where the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 10 mg and 200 mg.
54. The composition of claim 44, where the amount of at least one of the one or more than one HMG-CoA reductase inhibitor is between about 25 mg to 100 mg.
55. The composition of claim 44, further comprising one or more than one substance selected from the group consisting of a binding agent, a coloring agent, an enteric coating and a flavoring agent.
PCT/US2005/013175 2004-04-19 2005-04-18 Composition and method of decreasing renal ischemic damage WO2005102348A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012070040A1 (en) * 2010-11-26 2012-05-31 Technion Research And Development Foundation Ltd Compositions and methods for ameliorating renal dysfunction induced by renal hypoperfusion or acute kidney injury

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2363130B1 (en) 2006-07-05 2014-05-07 Takeda GmbH Combination of HMG-CoA reductase inhibitors atorvastatin or simvastatin with a phosphodiesterase 4 inhibitor, such as roflumilast for the treatment of inflammatory pulmonary diseases
KR102301639B1 (en) * 2015-01-23 2021-09-14 삼성전자주식회사 SoC, METHOD FOR MANAGING POWER OF THEREOF AND ELECTRONIC DEVICE
EP3575811A1 (en) 2018-05-28 2019-12-04 Koninklijke Philips N.V. Optical detection of a communication request by a subject being imaged in the magnetic resonance imaging system

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415556A (en) * 1980-12-23 1983-11-15 Dr. Franz Kohler Chemie Gmbh Protective solution for heart and kidney and process for its preparation
US20030139429A1 (en) * 2001-09-27 2003-07-24 Cohen David Saul Combinations
US20030181461A1 (en) * 2002-01-25 2003-09-25 Lautt Wilfred Wayne Use of phosphodiesterase antagonists to treat insulin resistance

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292658A (en) * 1989-12-29 1994-03-08 University Of Georgia Research Foundation, Inc. Boyd Graduate Studies Research Center Cloning and expressions of Renilla luciferase
JPH11515025A (en) * 1995-11-02 1999-12-21 ワーナー−ランバート・コンパニー Methods and pharmaceutical compositions for regulating lipid concentration
DE19944161A1 (en) * 1999-09-15 2001-03-22 Bayer Ag New combination for the treatment of sexual dysfunction
US6689807B1 (en) * 2000-06-08 2004-02-10 Caritas St. Elizabeth's Medical Center Of Boston, Inc. HMG CoA reductase inhibitors for promoting angiogenesis
LV12978B (en) * 2001-09-07 2003-05-20 Ivars Kalvins Pharmaceutical composition
US20030114469A1 (en) * 2001-09-27 2003-06-19 Cohen David Saul Combinations
ITMI20021012A1 (en) * 2002-05-13 2003-11-13 Giovanni Scaramuzzino COMBINATION OF AN HMG-COA REDUCTASE INHIBITOR AND AN ESTER NITRATE
AU2003265239A1 (en) * 2002-05-22 2003-12-19 Virginia Commonwealth University Protective effects of pde-5 inhibitors
BRPI0408500A (en) * 2003-03-17 2006-03-07 Pfizer Prod Inc Type 1 diabetes treatment with pde5 inhibitors
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415556A (en) * 1980-12-23 1983-11-15 Dr. Franz Kohler Chemie Gmbh Protective solution for heart and kidney and process for its preparation
US20030139429A1 (en) * 2001-09-27 2003-07-24 Cohen David Saul Combinations
US20030181461A1 (en) * 2002-01-25 2003-09-25 Lautt Wilfred Wayne Use of phosphodiesterase antagonists to treat insulin resistance

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1737465A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012070040A1 (en) * 2010-11-26 2012-05-31 Technion Research And Development Foundation Ltd Compositions and methods for ameliorating renal dysfunction induced by renal hypoperfusion or acute kidney injury

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